Hyperlipidemia is common among kidney transplant recipients. 1 This includes increased levels of the particularly atherogenic lipoprotein (a) and small, dense, low-density lipoprotein cholesterol (LDL-C). 2 Serum cholesterol levels have been shown to be an independent risk factor for graft failure and patient mortality as well as CVD. The National Kidney Foundation Task Force on Cardiovascular Disease recommends that kidney transplant recipients should be considered to be in the highest category of CVD risk, when applying the National Cholesterol Education Program guidelines for the treatment of dyslipidemias. 1. Kasiske BL. 1998;5(suppl 3):S142-S146. 2. Kasiske BL, et al. J Am Soc Nephrol . 1996;7:158-165.
Dislipidemia en el daño renal ok
EL PAPEL Y MANEJO DELA DISLIPIDEMIA EN EL DAÑO RENAL
Evidence from the General Population FRAMINGHAM STUDY (n= 5,209) ‡ 140 120 100CHD INCIDENCE per 1,000 80 60 40 20 0 <204 215 255 285 >295 SERUM CHOLESTEROL (mg/dL) ‡ W P Castelli Am J Med. 1984;
What are CHD Risk Equivalents Diabetes Chronic Kidney Disease Other clinical forms of atherosclerotic disease: – Peripheral arterial disease (PAD) – Abdominal aortic aneurysm (AAA) – Carotid artery disease Multiple ( single or total) risk factors that confer a 10-year risk for CHD > 20% NCEP ATP III RECOMMENDATIONS JAMA 2001; 285
ATP III Recommendations• Treatment should be started if LDL: – >100 mg/dL for CHD or CHD equivalent (10-year risk > 20%) – >130 mg/dL for 2+ risk factors (10-year risk 10-20%) – >160 mg/dL for 0-1 risk factor (10-year risk < 10%) NCEP ATP III RECOMMENDATIONS JAMA 2001; 285
WHY?• LEFT VENTRICULAR HYPERTROPHY: – Eccentric: fluid retention,anemia,AVF – Concentric: HTN,Aortic valvular disease• ATHEROSCLEROSIS: – Occlussive vascular, Ischemic Heart Disease and Increased Calcium deposition• ARTERIOSCLEROSIS: – Loss of elasticity of the Aorta and large vessels
Hay algunadiferencia entre lapoblación general ylos pacientes enhemodiálisis?
CVD in Hemodialysis Patients 100 10 Annual Mortality (%) 1 HD GP 0.1 0.01 0.001 25-34 35-44 45-54 55-64 65-74 AGE ( years)R. Foley, et al., Am J Kidney Dis 1998; 32 (Suppl 3)
Dyslipidemia and CKD facts Chronic Kidney Disease patients have 10-100 increased incidence of death due to cardiovascular complications compared with the general population. Foley et al., Am. Journal Kidney Diseases 1998; 32
Chronic Kidney Disease in the US STAGE GFR Prevalence Prevalence (ml/min/1.732) (%) 1 ~ 90 5,900,000 3.3 2 60-89 5,300,000 3.0 3 30-59 7,600,000 4.3 4 15-29 400,000 0.2 5 <15 or 300,000 0.1 dialysis CKD Guidelines. Am J Kidney Diseases 2002; 39 Suppl. 1
GENERAL CONCEPTS• Chronic Kidney Disease in the US: – 20 MILLION patients with CKD – Defined as a sustained GFR < 60 ml/min/1.73 m2 or patients with microalbuminuria of > 30 mg/dayCardiovascular disease is a modifiable risk factor• In CKD : – low cholesterol is associated with increased mortality – Statins can decrease –Δ GFR and decrease the CRP
GENERAL CONCEPTS II• Chronic Kidney Disease patients (CKD) lipid panel is characterized: – Decrease level of Apo A I + II leading to LOW levels of HDL – Increased level of Apo B leading to HIGH levels of LDL and VLDL WHY DECREASED LIPOLYTIC ENZYMES, POOR APOPROTEIN BINDING CAPACITY AND DECREASED UPTAKE OF LIPOPROTEINS
CKD and Cardiovascular Disease • Traditional risk • Non Traditional risk factors: factors: – Diabetes mellitus – Inflammation – Dyslipidemia – Oxidative stress – Hypertension – Malnutrition – Proteinuria – Anemia – Volume excess Framingham – Abnormal Ca/P – HyperhomocysteinemiaSarnak M J, et al. Cardiovascular disease and chronic renal disease:a new paradigm. Am J Kidney Dis. 2000;35 (4 suppl 1)
Lipids characteristics on CKD• General population- increased LDL• CKD patients: No correlation with LDL• Increased Lipoprotein a Lp (a) in CKD• Hemodialysis patients have a decreased catabolic rate for Lp (a)• Lp(a) and Apoprotein a are not well treated by statins. Kronenberg F. Dyslipidemia. ASN November 2003 San Diego, California
MORTALITY associated withDyslipidemiaLowrie at al., Am J Kid Disease 1990;15:458-482
REACTIVE OXIDATIVE SPECIES (ROS) • Increased production of ROS at the endothelium- Increased LDL oxidation • Oxidized LDL molecule is taken by macrophages leading to foam cells and calcification of the vessels • ROS inactivate nitric oxide: – Promoting pro-atherogenic events: • Increased WBC adherence • Platelet aggregation • Increasing CRPNiwa et al. ASN November 2003 San Diego, California
Daño Tubular: Oxidación de LDL con efecto Profibrótico y de proliferación Inflamación vascularcausando aterosclerosis de vasos.
HUMORAL CELLULAR Antidonor Ab MФ T Cell Endothelial cells Activation Hypertrophy Cell transformation ARTERY Allogeneic arterial injury during ARFunctional ActivationUpregulation of Class I &II MHC and Adhesion CD 8 T cellsmolecules: Platelet DGF,FGF, Perforin positiveMore endothelialdamage IL-1, IL-6Ab, complement, Cytolytic effectorCTL Fas mediated Fibrogenesis pathwayapoptosis RemodelingLoss of Barrier with Lipid trappinginflux of: fibrin,platelets,LDL, RBC’s Ground deposition IMMUNE MECHANISMS
Are there any special considerations fordyslipidemia treatment in CKD ?
Strength of Evidence for TreatingDyslipidemias in CKD CKD STAGE Strength of Evidence 1 (≥90) ***** 2 (60-89) **** 3 (30-59) *** 4 (< 30) ** 5 Dialysis * 5 Transplants ****
Therapy for Dyslipidemia• Are the STATINS effective and safe to treat Dyslipidemia among CKD patients?• Can we impact CARDIOVASCULAR mortality among CKD patients?• Other benefits of STATINS beyond Cholesterol control?
Potential Renoprotective Effects of Statins • Have been shown to provide pleiotropic effects independent of their proven beneficial effect on lowering cholesterol levels1 • Anti-inflammatory effects may be useful for the management of glomerulonephritis and diabetes mellitus • May have a potential immunomodulatory role in organ transplant recipients2 • Have been shown to enhance endothelial function2 • Have antioxidant effects21. Mason JC. Curr Opin Nephrol Hypertens. 2005;14:17-24.2. Jardine AG, Holdaas H, Fellstrom B, et al. Am J Transplant. 2004;4:988-995.
EFFICACY• Peritoneal dialysis experience: – Study: 177 PD patients treated for 4 weeks with Atorvastatin – Experienced ↓ of LDL-C ↓ of TG and significant of HDL-C compared to placebo arm. в Harris et al.,KI 2002;61• Hemodialysis experience: – All studies have confirmed ↓ of LDL-C є Van den Akker et al., Nephrol. 2003:16• Renal Transplantation experience: – ALERT STUDY: 5 year follow up of 200 patients treated with fluvastatin experienced a 32% reduction in LDL-C ф
TREATMENT OVERVIEWDYSLIPIDEMIA GOAL INITIATE INCREASE ALTERNATIVE (mg/dL)TG≥500 TG<500 Lifestyle Lifestyle Fibrate or niacin changes changes + fibrate or niacinLDL-C 100-129 LDL-C <100 Lifestyle Lifestyle Bile acid changes changes and sequestrant or low dose statin niacinLDL-C≥ 130 LDL-C <100 Lifestyle Lifestyle Bile acid changes and changes and sequestrant or low dose max-dose statin niacin statinTG ≥ 200 and Non-HDL-C Lifestyle Lifestyle Fibrate or niacinnon-HDL-C ≥ 30 <130 changes and changes and low dose max- dose statin statinTABLE 2
TREATMENT OVERVIEW cont.• FIBRATES: – Used to treat TG reducing by 30-50% – Fibrates are renal excreted – Increased risk of Rhabdomyolysis with statins – Increase serum creatinine• NICOTINIC ACID: – Most efficacious increasing HDL-C – No studies in CKD patients• BILE ACID SEQUESTRANTS: – Block intestinal reabsorption of bile acid and LDL-C
PHARMACOLOGY & SAFETY cont• Most statins are metabolized by the liver.• Get a baseline CPK• Myalgias: check CPK and hold the statin • Restart at 50% of the dose or use another • Consider use CoQ 10 • Do not use in patients with acute or chronic liver disease • Be careful with Calcineurin Inhibitors, warfarin, grapefruit juice
Statin Dose Adjustment in CKD Adjust for ↓ GFR ? AGENT 60-90 15-59 <15GFR Atorvastatin NO NO NO Atorv vs Prav (-36% vs-5.2% in CRP reduction) Fluvastatin ? ? ? Lovastatin NO ↓ to 50% ↓ to 50% Pravastatin NO NO NO Simvastatin ? ? ? Rosuvastatin NOAm J Kidney Dis 2003; 41 Suppl 3 ↓ to 50% ↓ to 25%
Other Dose Adjustments in CKD Adjust for ↓ GFR ? GFR 60-90 15-59 <15AGENTNicotinic acid NO NO ↓ to 50%Cholestipol NO NO NOCholestyramine NO NO NOCholesevelam NO NO NOAm J Kidney Dis 2003; 41 Suppl 3
Other Dose Adjustments in CKD Adjust for ↓ GFR ? GFR 60-90 59-15 15AGENTBezafibrate ↓ to 50% ↓ to 25% AvoidClofibrate ↓ to 50% ↓ to 25% AvoidCiprofibrate ? ? ?Fenofibrate ↓ to 50% ↓ to 25% AvoidGemfibrozil NO NO NO Am J Kidney Dis 2003; 41 Suppl 3
K/DOQ I GUIDELINES MAIN DIFFERENCE IS TO KEEP LDL-C LESS THAN 100 mg/dLNCEP- ATP III AJKD 2003; 41
Atorvastatin & CKD Progression • Open label, randomized, controlled study • 56 patients with idiopathic membranous glomerulonephritis – Proteinura > 1 g/24 hrs – All treated with ACEi for 1 year then: – Atorvastatin 40 mg vs. no treatment • Outcome of Atorvastatin vs. control at 1 year: – Cr clearance: 49.8±1.7 vs. 44.2±1.5 mL/min (p<0.05) – Urine protein: 1.5 vs. 2.2 g/24 hrs (p<0.01) S Bianchi, et al., Am J Kidney Dis 2003; 41:565
Dyslipidemia in Renal Transplant Recipients % in Kidney Transplant Lipid Abnormality Recipients ↑ Total cholesterol: >240 mg/dL (6.21 60% mmol/L) ↑ LDL-C >130 mg/dL (3.36 mmol/L) 60% ↑ Triglycerides 35% HDL-C <35 mg/dL (0.9 mmol/L) 15%Kasiske BL. Am J Kidney Dis. 1998;5(Suppl 3):S142-S146.Kasiske BL, et al. J Am Soc Nephrol. 1996;7:158-165.
IMPROVEMENTS• Chronic Kidney Disease Stages 2-4 – CARE STUDY – Cholesterol and Recurrent Events – Randomized, double-blinded, placebo contolled trial – 1,700 patients with crcl < 75 ml/min experienced a ↓ 28% in AMI and fatal CHD compared with the untreated group Tonelli at al., Annals of Internal Medicine 2003;138:98-104
Lipid Lowering in CKD Patients in theCholesterol and Recurrent Events (CARE)Study 4159 with AMI and cholesterol < 240 mg/dL 3384 with MDRD-calculated eGFR 690 with eGFR < 60 ml/min/1.73m2 MDRM eGFR Slowing of GFR P-value (ml.min/1.73m2) decline (ml.min/1.73m2/year) <60 0.1 0.49 <50 0.6 0.07 <40 2.5 0.001 M Tonelli, et al., J Am Soc Nephrol 2003;14:1605
IMPROVEMENTS• CKD 5: – Selinger et al., KI 2002; 61 – HMG CoA reductase inhibitors are associated with reduced mortality in ESRD patients.• RENAL Transplant Experience: – ALERT STUDY: – Tread toward ↓incidence of cardiac death, non fatal MI and less coronary aa procedures on the Fluvastatin group vs. control.
OTHER STATINS EFFECTS• Anti-inflammatory effects: – Decreased the levels of atherogenic oxidazed LDL-C – ↓ C Reactive Protein• Reducing Progression of CKD: – Statins can ↓ the –Δ GFR and decrease the proteinuria Kasiske B. et al., KI 2001; 59 Tonelli et al., JASN 2003; 14 Bianchi et al., AJKD 2003; 41
STATINS SIDE EFFECTS• Liver function test abnormalities• Rhabdomyolysis• Myalgias• Proteinuria
OTHER STUDIES in the pipeline • DIE DEUTSCHE DIABETES DIALYSE 4D: – Evaluated in a prospective, randomized, placebo controlled trail- 1,200 HD /Type II DM pts on atorvastatin 20 mg/day • SHARP: – The Study of Heart and Renal Protection – Prospective, randomized, placebo controlled2007 trail- 6,000 predialysis and 3,000 dialysis pts – Plan is to evaluate the efficacy of Ezetimide and Simvastatin vs. placebo • AURORA: – prospective, randomized, placebo controlled trail- 3,000 HD patients on rosuvastatin
Deutsche Diabetes-Dialyse-Studie 60%PRIMARY COMPOSITE END POINTS(%)CUMULATIVE INCIDENCE OF THE Atorvastatin vs. placebo 2 1 3 6 years
CONCLUSIONS• CKD PATIENTS ARE A CHALLENGE DUE TO THEIR COMPLEX MEDICAL PROBLEMS AND BECAUSE THE TREATMENT OF THEIR DYSLIPIDEMIA EVOLVES WITH THEIR DISEASE RAPID TURNOVER AND CHANGES• THERE IS INSUFFICIENT DATA TO ASSESS THE USE OF THESE AGENTS USED TO TREAT DYSLIPIDEMIAS IN RENAL FAILURE PATIENTS.